A polycomb repression signature in metastatic prostate cancer predicts cancer outcome

被引:252
作者
Yu, Jindan
Yu, Jianjun
Rhodes, Daniel R.
Tomlins, Scott A.
Cao, Xuhong
Chen, Guoan
Mehra, Rohit
Wang, Xiaoju
Ghosh, Debashis
Shah, Raja B.
Varambally, Sooryanarayana
Pienta, Kenneth J.
Chinniaiyan, Arul M.
机构
[1] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Dept Pathol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Sch Med, Dept Biostat, Ann Arbor, MI 48109 USA
[5] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA
[6] Univ Michigan, Sch Med, Bioinformat Program, Ann Arbor, MI 48109 USA
[7] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA
关键词
D O I
10.1158/0008-5472.CAN-07-2498
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys(27) of historic 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a "Polycomb repression signature" composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival.
引用
收藏
页码:10657 / 10663
页数:7
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